PHYSOSTIGMINE  SALICYLATE  INJECTION  USP  (Physostigmine  Salicylate) is a derivative of the Calabar bean, and its active moiety, physostigmine, is also known as eserine. Chemically, Physostigmine Salicylate is Pyrrolo[2,3-b]indol-5-ol,1,2,3,3a,8,8a-hexahydro-1,3a, 8-trimethyl-, methylcarbamate (ester),(3aS-cis)-, mono-(2-hydroxybenzoate). The molecular formula is C₁₅H₂₁N₃O₂·C₇H₆O₃  and molecular weight is 413.47.

STRUCTURAL FORMULA :  
Its structural formula is :

PHYSOSTIGMINE  SALICYLATE  INJECTION  USP  is a sterile, clear, colourless solution filled in amber ampoule of suitable size.

COMPOSITION :
Each ml contains :
Physostigmine Salicylate USP                    1 mg
Benzyl Alcohol USP                             2.0 % w/v
(as preservative)
Water for Injection USP                                  q.s.

ACTIONS : 
Physostigmine Salicylate is a reversible anticholinesterase which effectively increases the concentration of acetylcholine at the sites of cholinergic transmission. The action of acetylcholine is normally very transient because of its hydrolysis by the enzyme,
acetylcholinesterase. Physostigmine Salicylate inhibits the destructive action of acetylcholinesterase and thereby prolongs and exaggerates the effect of the acetylcholine. Physostigmine Salicylate contains a tertiary amine and easily penetrates the blood brain barrier, while an anticholinesterase, such as neostigmine, which has a quaternary ammonium ion is not capable of crossing the barrier. Physostigmine Salicylate can reverse both central and peripheral anticholinergia. The anticholinergic syndrome has both central and peripheral signs and symptoms. Central toxic effects include anxiety, delirium, disorientation, hallucinations, hyperactivity and seizures. Severe poisoning may produce coma, medullary paralysis and death. Peripheral toxicity is characterized by tachycardia, hyperpyrexia, mydriasis, vasodilation, urinary retention, diminution of gastrointestinal motility, decrease of secretion in salivary and sweat glands, and loss of secretions in the pharynx, bronchi, and nasal passages.

Dramatic reversal of the effects of anticholinergic symptoms can be expected in minutes after the intravenous administration of Physostigmine Salicylate, if the diagnosis is correct and the patient has not suffered anoxia or other insult. The duration of action of Physostigmine Salicylate is relatively short, approximately 45 to 60 minutes. Numerous drugs and some plants produce the anticholinergic syndrome either directly or as a side effect; this undesirable or potentially dangerous phenomenon may be brought about by either therapeutic doses or overdoses of the drugs. Such drugs include among others, atropine, other derivatives of the belladonna alkaloids, tricyclic antidepressants, phenothiazines, and antihistamines.

PHARMACOKINETICS : 
Distribution : Easily penetrates the blood-brain barrier.
Biotransformation : Rapidly hydrolyzed by cholinesterases.
Time to peak effect : Intramuscular - 20 to 30 minutes.
Intravenous - Within 5 minutes.
Duration of action : Intramuscular and intravenous - 30 to 60 minutes.
Elimination : Very small amounts eliminated in urine; largely destroyed in body by hydrolysis.

INDICATIONS : 
PHYSOSTIGMINE  SALICYLATE  INJECTION  USP is indicated to reverse the effect upon the central nervous system, caused by clinical or toxic dosages of drugs capable of producing the anticholinergic syndrome.

Administration  :
PHYSOSTIGMINE  SALICYLATE  INJECTION  USP is intended for intramuscular or intravenous administration.

INSTRUCTIONS  FOR  USE  OF  AMPOULE :
The ampoule used in this product is equipped with O.P.C (One Point Cut) opening system. No ampoule file is needed to open the ampoule. The neck of the ampoule is prescored at the point of constriction. A coloured dot on the ampoule head helps to orientate the ampoule. Take the ampoule and face the coloured dot. Let the solution at the head of the ampoule to flow down by shaking or a gentle stroke. The ampoule opens easily by placing the thumb on the coloured dot and gently pressing downwards as shown.

Dosage :
Past Anaesthesia Care : 
0.5 to 1.0 mg intramuscularly or intravenously. INTRAVENOUS ADMINISTRATION  SHOULD  BE  AT  A  SLOW  CONTROLLED  RATE  OF  NO  MORE THAN 1 MG  PER  MINUTE. Dosage may be repeated at intervals of 10 to 30 minutes if desired patient response is not obtained. 

Overdosage  of  drugs  that  cause  anticholinergic :
2.0 mg intramuscularly or INTRAVENOUSLY  AT  SLOW  CONTROLLED  RATE. Dosage may be repeated if life threatening signs, such as arrhythmia, convulsions or coma occurs.

Paediatric dosage :
Recommended dosage is 0.02 mg/kg; intramuscularly or by slow intravenous injection, no more than 0.5 mg per minute. If the toxic effects persist, and there is no sign of cholinergic effects, the dosage may be repeated at 5 to 10 minute intervals until a therapeutic effect is obtained or a maximum of 2 mg dosage is attained.

General Advice :
• Inject slowly; do not exceed a rate of 1 mg/min for adults and 0.5 mg/min for children. Rapid administration can cause bradycardia or hypersalivation leading to respiratory difficulties and possible convulsions.
• If excessive symptoms of salivation, emesis, urination and defecation occur, terminate the use of physostigmine. If excessive sweating or nausea occur, reduce the dosage.
• Keep atropine at hand because it is an antagonist and antidote for physostigmine.

CONTRAINDICATIONS : 
PHYSOSTIGMINE  SALICYLATE  INJECTION  USP should not be used in the presence of asthma, gangrene, diabetes, cardiovascular disease, mechanical obstruction of the intestine or urogenital tract or any vagotonic state, and in patients receiving choline esters and depolarizing neuromuscular blocking agents (decamethonium, succinylcholine). For post-anaesthesia, the concomitant use of atropine with physostigmine salicylate is not recommended, since the atropine antagonizes the action of physostigmine.

WARNINGS :
PHYSOSTIGMINE  SALICYLATE  INJECTION  USP contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than non-asthmatic people. PHYSOSTIGMINE  SALICYLATE  INJECTION  USP contains benzyl alcohol as preservative. Benzyl alcohol has been reported to be associated with a fatal “Gasping Syndrome” in premature infants. Symptoms include a striking onset of gasping syndrome, hypotension, bradycardia and cardiovascular collapse. Physostigmine should not be used if a patient has QRs or QTc prolongation.

PRECAUTIONS : 
Because of the possibility of hypersensitivity in an occasional patient, atropine sulfate injection should always be at hand since it is an antagonist and antidote for physostigmine.

 Pregnancy : Category C